Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia (ODYSSEY HIGH FH)

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The study was conducted at 33 centers in 5 countries. A total of 206 participants were screened between June 2012 and May 2013, 99 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.

Pre-assignment Details

Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:2 ratio (placebo:alirocumab) after confirmation of selection criteria. 107 participants were randomized.

Arm/Group Title

Placebo Q2W

Alirocumab 150 mg Q2W

Arm/Group Description

Placebo for alirocumab subcutaneous...

Alirocumab 150 mg SC injection Q2W ...

Arm/Group Description

Placebo for alirocumab subcutaneous (SC) injection every two weeks (Q2W) on top of stable lipid-modifying therapy (LMT) for 78 weeks.

Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post­baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model (ITT analysis).

Time Frame

From Baseline to Week 52

Outcome Measure Data Outcome Measure Data

Analysis Population Description

Analysis Population Description

ITT population: all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on- or off- treatment.

Arm/Group Title

Placebo Q2W

Alirocumab 150 mg Q2W

Arm/Group Description:

Placebo for alirocumab SC injection...

Alirocumab 150 mg SC injection Q2W ...

Arm/Group Description:

Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.

Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.

Overall Number of Participants Analyzed

35

71

Least Squares Mean (Standard Error)

Unit of Measure: percent change

-6.6
(4.9)

-45.7
(3.5)

Statistical Analysis 1
Statistical Analysis 1

Statistical Analysis Overview

Comparison Group Selection

Placebo Q2W, Alirocumab 150 mg Q2W

Comments

Alirocumab group was compared to placebo group using an appropriate contrast statement.

Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection (on-treatment analysis).

Time Frame

From Baseline to Week 52

Outcome Measure Data Outcome Measure Data

Analysis Population Description

Analysis Population Description

Modified ITT (mITT) population: all randomized and treated participants with one baseline and at least one post-baseline calculated LDL-C value on-treatment.

Arm/Group Title

Placebo Q2W

Alirocumab 150 mg Q2W

Arm/Group Description:

Placebo for alirocumab SC injection...

Alirocumab 150 mg SC injection Q2W ...

Arm/Group Description:

Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.

Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.

Overall Number of Participants Analyzed

35

71

Least Squares Mean (Standard Error)

Unit of Measure: percent change

-6.6
(5)

-45.5
(3.5)

Statistical Analysis 1
Statistical Analysis 1

Statistical Analysis Overview

Comparison Group Selection

Placebo Q2W, Alirocumab 150 mg Q2W

Comments

A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.

Adjusted means and standard errors at Week 24 from a multiple imputati...

Description

Adjusted means and standard errors at Week 24 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Time Frame

From Baseline to Week 52

Outcome Measure Data Outcome Measure Data

Analysis Population Description

Analysis Population Description

ITT population.

Arm/Group Title

Placebo Q2W

Alirocumab 150 mg Q2W

Arm/Group Description:

Placebo for alirocumab SC injection...

Alirocumab 150 mg SC injection Q2W ...

Arm/Group Description:

Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.

Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.

Overall Number of Participants Analyzed

35

71

Mean (Standard Error)

Unit of Measure: percent change

-8.7
(5)

-23.5
(3.7)

Statistical Analysis 1
Statistical Analysis 1

Statistical Analysis Overview

Comparison Group Selection

Placebo Q2W, Alirocumab 150 mg Q2W

Comments

Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).

Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Time Frame

From Baseline to Week 52

Outcome Measure Data Outcome Measure Data

Analysis Population Description

Analysis Population Description

ITT population.

Arm/Group Title

Placebo Q2W

Alirocumab 150 mg Q2W

Arm/Group Description:

Placebo for alirocumab SC injection...

Alirocumab 150 mg SC injection Q2W ...

Arm/Group Description:

Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.

Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Time Frame

From Baseline to Week 52

Outcome Measure Data Outcome Measure Data

Analysis Population Description

Analysis Population Description

ITT population.

Arm/Group Title

Placebo Q2W

Alirocumab 150 mg Q2W

Arm/Group Description:

Placebo for alirocumab SC injection...

Alirocumab 150 mg SC injection Q2W ...

Arm/Group Description:

Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.

Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Time Frame

From Baseline to Week 52

Outcome Measure Data Outcome Measure Data

Analysis Population Description

Analysis Population Description

ITT population.

Arm/Group Title

Placebo Q2W

Alirocumab 150 mg Q2W

Arm/Group Description:

Placebo for alirocumab SC injection...

Alirocumab 150 mg SC injection Q2W ...

Arm/Group Description:

Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.

All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit in the study regardless of seriousness or relationship to study drug.

Adverse Event Reporting Description

Reported adverse events are treatment-emergent that is AEs that developed/worsened during the 'treatment-emergent period' (from the first double-blind injection up to the day of the last injection + 70 days or up to first intake in the extension study, whichever came first).

Arm/Group Title

Placebo Q2W

Alirocumab 150 Q2W

Arm/Group Description

Participants exposed to placebo Q2W...

Participants exposed to Alirocumab ...

Arm/Group Description

Participants exposed to placebo Q2W on top of stable LMT (mean exposure of 71 weeks).

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts
the PI's rights to discuss or publish trial results after the trial is completed.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.